White matter microstructure and its relation to clinical features of obsessive–compulsive disorder: findings from the ENIGMA OCD Working Group

Microstructural alterations in cortico-subcortical connections are thought to be present in obsessive–compulsive disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Here we investigated microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. We analyzed diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA OCD Working Group, in a cross-sectional case-control magnetic resonance study. We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen’s d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. Adult OCD patients showed significant FA reduction in the sagittal stratum (d = −0.21, z = −3.21, p = 0.001) and posterior thalamic radiation (d = −0.26, z = −4.57, p < 0.0001). In the sagittal stratum, lower FA was associated with a younger age of onset (z = 2.71, p = 0.006), longer duration of illness (z = −2.086, p = 0.036), and a higher percentage of medicated patients in the cohorts studied (z = −1.98, p = 0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to controls. Our findings of microstructural alterations in projection and association fibers to posterior brain regions in OCD are consistent with models emphasizing deficits in connectivity as an important feature of this disorder

Structural neuroimaging biomarkers for obsessive-compulsive disorder in the ENIGMA-OCD consortium: medication matters

No diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Here, we aimed to identify magnetic resonance imaging (MRI) biomarkers for OCD, using 46 data sets with 2304 OCD patients and 2068 healthy controls from the ENIGMA consortium. We performed machine learning analysis of regional measures of cortical thickness, surface area and subcortical volume and tested classification performance using cross-validation. Classification performance for OCD vs. controls using the complete sample with different classifiers and cross-validation strategies was poor. When models were validated on data from other sites, model performance did not exceed chance-level. In contrast, fair classification performance was achieved when patients were grouped according to their medication status. These results indicate that medication use is associated with substantial differences in brain anatomy that are widely distributed, and indicate that clinical heterogeneity contributes to the poor performance of structural MRI as a disease marker

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte–myelin dysfunction

Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte–myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte–myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption of white matter integrity compared with familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) derived case oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro. Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1;11) oligodendrocyte progenitors were significantly reduced when compared with controls. Thus we provide evidence that the t(1;11) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte–myelin dysfunction

MK-Curve improves sensitivity to identify white matter alterations in clinical high risk for psychosis

Diffusion kurtosis imaging (DKI) is a diffusion MRI approach that enables the measurement of brain microstructural properties, reflecting molecular restrictions and tissue heterogeneity. DKI parameters such as mean kurtosis (MK) provide additional subtle information to that provided by popular diffusion tensor imaging (DTI) parameters, and thus have been considered useful to detect white matter abnormalities, especially in populations that are not expected to show severe brain pathologies. However, DKI parameters often yield artifactual output values that are outside of the biologically plausible range, which diminish sensitivity to identify true microstructural changes. Recently we have proposed the mean-kurtosis-curve (MK-Curve) method to correct voxels with implausible DKI parameters, and demonstrated its improved performance against other approaches that correct artifacts in DKI. In this work, we aimed to evaluate the utility of the MK-Curve method to improve the identification of white matter abnormalities in group comparisons. To do so, we compared group differences, with and without the MK-Curve correction, between 115 individuals at clinical high risk for psychosis (CHR) and 93 healthy controls (HCs). We also compared the correlation of the corrected and uncorrected DKI parameters with clinical characteristics. Following the MK-curve correction, the group differences had larger effect sizes and higher statistical significance (i.e., lower p-values), demonstrating increased sensitivity to detect group differences, in particular in MK. Furthermore, the MK-curve-corrected DKI parameters displayed stronger correlations with clinical variables in CHR individuals, demonstrating the clinical relevance of the corrected parameters. Overall, following the MK-curve correction our analyses found widespread lower MK in CHR that overlapped with lower fractional anisotropy (FA), and both measures were significantly correlated with a decline in functioning and with more severe symptoms. These observations further characterize white matter alterations in the CHR stage, demonstrating that MK and FA abnormalities are widespread, and mostly overlap. The improvement in group differences and stronger correlation with clinical variables suggest that applying MK-curve would be beneficial for the detection and characterization of subtle group differences in other experiments as well

Ultrafast laser plasma doping of Er3+ ions in silica-on-silicon for optical waveguiding applications

An ultrafast laser plasma doping (ULPD) technique is used for high concentration doping of erbium ions into silica-on-silicon substrate. The method uses a femtosecond laser to ablate material from TeO2-ZnONa2O-Er2O3 (Er-TZN) target glass. The laser generated plasma modifies the silica network, producing high index contrast optical layer suited to the production of on-chip integrated optical circuits. Cross-sectional analysis using scanning electron microscope with energy dispersive xray spectroscopy revealed homogeneous intermixing of the host silica with Er-TZN, which is unique to ULPD. The highly doped layer exhibits spectroscopic characteristics of erbium with photoluminescence lifetimes ranging from 10.79 ms to 14.07 ms

Doxorubicin kinetics and effects on lung cancer cell lines using in vitro Raman micro-spectroscopy: binding signatures, drug resistance and DNA repair

International audienceRaman micro-spectroscopy is a non-invasive analytical tool, whose potential in cellular analysis and monitoring drug mechanisms of action has already been demonstrated, and which can potentially be used in pre-clinical and clinical applications for the prediction of chemotherapeutic efficacy. To further investigate such potential clinical application, it is important to demonstrate its capability to differentiate drug mechanisms of action and cellular resistances. Using the example of Doxorubicin (DOX), in this study, it was used to probe the cellular uptake, signatures of chemical binding and subsequent cellular responses, of the chemotherapeutic drug in two lung cancer cell lines, A549 and Calu-1. Multivariate statistical analysis was used to elucidate the spectroscopic signatures associated with DOX uptake and subcellular interaction. Biomarkers related to DNA damage and repair, and mechanisms leading to apoptosis were also measured and correlated to Raman spectral profiles. Results confirm the potential of Raman spectroscopic profiling to elucidate both drug kinetics and pharmacodynamics and differentiate cellular drug resistance associated with different subcellular accumulation rates and subsequent cellular response to DNA damage, pointing towards a better understanding of drug resistance for personalised targeted treatment